Gammopathy is a collective term referring to various diseases or conditions characterized by an abnormal level of immunoglobulin, termed paraprotein, in affected patients. In monoclonal gammopathies, one specific monoclonal immunoglobulin is produced in excess amounts. Gammopathies can be of malignant or non-malignant nature. Multiple myeloma (MM), sclerotic myeloma, Waldenström macroglobulinemia (WM), immunocytic lymphoma, follicular lymphoma, B cell lymphoma (e.g. immunoblastoma), and chronic B cell lymphocytic leukemia associated with IgM monoclonal proteins, are all examples of malignant gammopathies. Benign gammopathies are collectively referred to as gammopathies of undetermined significance (MGUS).
Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease (after Otto Kahler) accounts for 1% of all malignancies, and for over 10% of the hematological malignancies with a prevalence peak at around 70 years of age. It is the second most common hematologic malignancy in the United States (Katzel et al, 2007) and is regarded as incurable. However, remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants. The disease is characterized by neoplastic proliferation of a single plasma cell clone producing a monoclonal immunoglobulin termed paraprotein, M-protein or M-component (Kyle, 1994), which can be detected as a predominant spike in the densitometric analysis of the y globulin fraction area or as a sharp dominant band in immunofixation (Jeppsson et al, 1979). The identification of the antigenic stimuli of such B-cell neoplasms might have considerable impact on our understanding of the pathogenesis of MM, because a causal relationship between these neoplasms and antigenic stimulation has been suggested.
Waldenström macroglobulinemia (WM) is a condition characterized by the presence of a high level of a monoclonal immunoglobulin of the IgM type, elevated serum viscosity, and the presence of a lymphoplasmacytic infiltrate in the bone marrow. WM is a clonal disorder of B lymphocytes and is considered to be a lymphoplasmacytic lymphoma as defined by the World Health Organization (WHO) classification. The clinical manifestations of this condition result from the presence of the paraprotein and malignant lymphoplasmacytic cell infiltration of the bone marrow and other tissue sites. WM is similar to MM, except that organomegaly is common in Waldenström macroglobulinemia and is uncommon in multiple myeloma and lytic bone disease and renal disease are uncommon in Waldenström macroglobulinemia but are common in multiple myeloma.
Malignant gammopathies are often preceded by benign gammopathies. For example, MM is often preceded by monoclonal gammopathy of undetermined significance (MGUS), a benign disorder with a strikingly elevated monoclonal immunoglobulin (or paraprotein-) level of less than 30 g/L in individuals lacking evidence of MM or other lymphoproliferative malignancies. Long-term follow-up of patients with MGUS reveals a 1% to 3% annual risk of developing MM or, to a lesser extent, other lymphoproliferative malignancies. Although investigators have recently described potential models of pathogenesis of gammopathies, such as MGUS and MM, it is unknown whether non-malignant gammopathies precede all malignant gammopathies, for example if all cases of MM are preceded by MGUS, or if malignant gammopathies, for example MM, can arise de novo without preceding MGUS (Landgren et al, 2006).
Paraproteins or monoclonal immunoglobulins characteristic for gammopathies may consist of intact immunoglobulin molecules or of heavy or light chains only. Depending on their rate of production and/or secretion they may accumulate in the serum and/or urine of patients. Their presence in the circulation may remain silent, as in MGUS, or may lead to clinical syndromes such as hyperviscosity, acrocyanosis, cold hemagglutination, hemolysis and hemorrhagic manifestations. Their tissue deposition may be localized, with the kidney being the most frequent target as in myeloma cast nephropathy or systemic, as in AL amyloidosis where heart, liver, nerves, tongue are usual targets, in addition to the kidneys.
So far, two systematic approaches were pursued to characterize the antigenic targets of paraproteins characteristic for gammopathies. One approach was founded on screening cDNA expression libraries of different origins for high affinity binding partners of paraproteins (Preuss et al, 2007). These led to the identification of antigenic targets with affinity greater 1:108 such as autoantigenic targets like TPP2 (titer) ˜1010) or (IGFBP-2) (titer ˜109), or food antigens (porcine kinesin, titer ˜109). However, all these targets were individually specific and reacted with the paraprotein of only one patient.
Another approach was the usage of phage display random peptide libraries with the goal to identify binding epitopes which should allow the identification of the antigen by searching non-redundant protein databases. This attempt also identifies single protein events like human cytomegalovirus envelop proteins (titer ˜2×103) (Sompuram et al, 2008) or only some consensus epitopes with titers ˜105, but no corresponding proteins could be identified (Szecsi et al, 1999).
To date, antigenic targets of paraproteins were discovered accidentally due to clinical symptoms caused by the paraprotein (e.g., chronic cold agglutinin disease or cryoglobulinemia (Seligmann & Brouet, 1990) or bleeding disorder (Colwell et al, 1997), because of interference of the paraprotein with laboratory tests ordered for the clinical work-up of the patient (e.g., HIV-1 p24 antigen in an HIV-infected patient with myeloma (Konrad et al, 1993)) or by screening paraproteins against predefined antigens (e.g., anti-streptolysin, anti-DNA, anti-IgG (Seligmann & Brouet, 1990)).